ABSTRACT Development and progression of cancer occurs in spite of anti-tumorigenic effects of Type 1 interferon cytokines (IFN1, including IFN? and IFN?). IFN1 counteract tumor development and progression directly (by suppression of malignant cells) and indirectly (by stimulation of anti-tumor immunity). Our work in the past funding period revealed that the integrated stress response (ISR) induced in the tumor microenvironment help malignant and benign tumor cells to evade the anti-tumorigenic effects of IFN1. We found that ISR-driven inactivation of IFN1 receptor IFNAR1 deprives tumor cells from ability to respond to IFN1 and plays an important role in tumor growth and progression. Furthermore, our work revealed an important role of IFNAR1 inactivation in the ISR-induced death of activated intra-tumoral cytotoxic T lymphocytes and, accordingly, in generation of the immune privileged niche that helps to overcome anti-tumor immunity. Our new pilot experiments also suggested that inactivation of IFNAR1 decreases the tumoricidal activity of cytotoxic T lymphocytes and undermines the efficacy of adoptive transfer of chimeric antigen receptor T cells and of inhibitors of immune checkpoints. New preliminary studies from our group and our collaborators (Projects 1-2) also revealed that additional innovative mechanisms promoting tumorigenesis depend on inactivation of the IFNAR1 pathway in a manner that involve ATF4 and its regulated miRNAs (e.g. miR-211 and miR-217) and include the suppression of translation of the mRNAs for IFNAR1 and the IFN-stimulated genes (IGSs). In our current proposal, we aim to define these mechanisms and target them to augment anti-cancer therapies. We will test an integrated hypothesis that, in the tumor microenvironment, the ISR-driven inactivation of the IFNAR1 pathway in the cytotoxic T lymphocytes plays a pivotal role in tumor growth and progression. Furthermore, efforts to restore IFNAR1 signaling can stimulate anti-cancer immune responses and improve the outcome of therapeutic approaches. To test this hypothesis, we propose to delineate the mechanisms underlying ISR-induced IFNAR1- dependent and independent inactivation of the IFN1 pathway and its role in the loss of viability of intratumoral cytotoxic lymphocytes and the generation of the immune privileged niches (Aim 1). We will also delineate the mechanisms underlying ISR-driven inactivation of the tumoricidal activities of cytotoxic T lymphocytes and determine whether targeting these mechanisms can augment anti-cancer immunity (Aim 2). Completion of these studies should improve our knowledge on the role of ISR in generating the immune privileged niches that provide safe harbor for malignant cells and drive tumor growth and progression. Furthermore, identification and characterization of the mechanisms leading to IFNAR1 pathway inactivation will enable us to identify specific targets for improving the efficacy of anti-cancer immune therapies.